LOW DOSE INTERLEUKIN-2 THERAPY MODULATES AUTOIMMUNITY AND RENAL INJURY IN EXPERIMENTAL ANTI-MYELOPEROXIDASE GLOMERULONEPHRITIS

J DICK1, P GAN1, M ALIKHAN1, R KITCHING1, S HOLDSWORTH1
1Monash University , Clayton , Australia

Aim: To determine the potential of low dose IL-2 therapy in experimental ANCA-associated vasculitis (AAV).
Background: Low dose IL-2 expands regulatory T cells (Tregs) and is a potential therapy for autoimmune disease.
Methods: Anti-MPO autoimmunity was induced in C57BL/6 mice by immunisation with MPO. T cell mediated anti-MPO glomerulonephritis was triggered on day 16 in immunised mice by anti-GBM globulin, and MPO-ANCA induced glomerulonephritis by passive transfer of MPO-ANCA/LPS. Mice were treated with IL-2, 25,000units/day for 7 days. Immune responses were measured by flow cytometry, ELISPOT and ELISA.
Results: IL-2 increased splenic Tregs (26.2±0.8vs17±0.3 %CD4+, P<0.0001) and up-regulated expression of the suppressive markers CTLA4 and PD-1. Mice treated with IL-2 before MPO immunisation developed attenuated Th1 and Th17 autoimmunity, measured by splenocyte ELISPOT (IFN-γ 68±12vs123±16 spots, P=0.009; IL-17A 31±7vs70±12 spots P=0.003). This was associated with reduced segmental glomerular necrosis (24±4vs48±6%, P=0.0054) and reduced albuminuria. IL-2 pre-treatment did not alter humoral immunity.Treatment with IL-2 before passive transfer of MPO-ANCA/LPS increased numbers of intra-renal Tregs (2316±402vs1246±170 CD4+Foxp3+cells/kidney, P=0.02) and reduced intra-renal F4/80hiCCR2hi inflammatory macrophages (P<0.01).To evaluate therapy in established autoimmunity, mice were treated with IL-2 12 days after MPO immunisation. Although splenic Tregs were expanded, T effector response was also enhanced with more IFN-γ and IL17A producing cells (both P<0.01). Conversely, IL-2 therapy attenuated ANCA production (0.49±0.04 vs 0.29±0.03 OD480, P=0.0019), this was associated with suppressed T follicular helper cell generation. The net effect of IL-2 therapy was exacerbation of glomerular necrosis (87±3vs26±4%, P<0.0001) and increased albuminuria.
Conclusions: IL-2 has diverse and context specific effects on cellular and humoral autoimmunity. The potentiation of T effector responses in established autoimmunity may limit its utility in AAV.


Biography:
Dr Jonathan Dick studied medicine at the University of Oxford and University College London before training in internal medicine and nephrology in London. He recently completed a PhD at Monash University supervised by Professors Steve Holdsworth and Richard Kitching on novel roles for complement in pre-clinical models of ANCA-vasculitis.

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